GO:0140613 P-type manganese transporter activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0140613 defines P-type manganese transporter activity, a primary active transport function that uses ATP hydrolysis to move Mn2+ across membranes against its concentration gradient.
• The reaction catalyzed is ATP + H2O + Mn2+(in) = ADP + H+ + Mn2+(out) + phosphate, coupling manganese efflux to ATP consumption.
• P-type ATPases form a large superfamily of phosphorylated intermediate transporters, and manganese-transporting members are critical for metal homeostasis in bacteria, plants, and humans [2,3].
• In Mycobacterium tuberculosis, efflux pumps including P-type ATPases contribute to metal resistance and survival within host macrophages.
• In plants, P-type ATPases such as ECA and ACA isoforms help manage manganese and calcium homeostasis under stress conditions [5,8].
• Dysregulation of manganese transport is linked to Parkinson's disease through ATP13A2, a lipid-regulated P-type ATPase.
Description
P-type manganese transporter activity (GO:0140613) is a molecular function that enables the ATP-dependent movement of manganese ions (Mn2+) across a membrane, from the inside of a cell or compartment to the outside. This activity belongs to the P-type ATPase superfamily, whose members form a phosphorylated intermediate during the transport cycle and are widespread across all domains of life. Manganese is an essential trace metal that serves as a cofactor for enzymes involved in antioxidant defense, photosynthesis, and neurotransmitter synthesis, but it becomes toxic when it accumulates excessively. Therefore, organisms must tightly regulate Mn2+ uptake and efflux, and P-type manganese transporters are central to this balance. Researchers study GO:0140613 because it connects membrane bioenergetics to metal homeostasis, with direct implications for bacterial pathogenesis, plant nutrition, and human neurodegenerative disease [1,3,5]. In Mycobacterium tuberculosis, efflux systems that include P-type ATPases help the pathogen resist host-imposed metal stress and antibiotics. In plants, P-type ATPases contribute to manganese distribution and antioxidant responses under excess manganese. In humans, the P-type ATPase ATP13A2 is linked to Parkinson's disease and is regulated by lipid environment. Understanding the molecular mechanism, regulation, and disease relevance of P-type manganese transporter activity is therefore a high-priority research area [2,3].
P-type manganese transporter activity At A Glance
| GO ID | GO:0140613 |
|---|---|
| GO term | P-type manganese transporter activity |
| Ontology | molecular_function |
| Synonym | None listed in QuickGO |
| Major function | ATP-dependent efflux of Mn2+ across a membrane |
| Reaction | ATP + H2O + Mn2+(in) = ADP + H+ + Mn2+(out) + phosphate |
| Protein family | P-type ATPase superfamily |
| Cellular location | Integral membrane proteins (plasma membrane, organelle membranes) |
| Representative genes | ATP13A2, bacterial efflux ATPases, plant ECA/ACA isoforms |
What Is GO:0140613?
According to the Gene Ontology, GO:0140613 (P-type manganese transporter activity) enables the transfer of a solute or solutes from one side of a membrane to the other according to the reaction: ATP + H2O + Mn2+(in) = ADP + H+ + Mn2+(out) + phosphate. In other words, it is a primary active transport activity that uses the energy of ATP hydrolysis to pump manganese ions (Mn2+) out of a cell or organelle, generating ADP, inorganic phosphate, and protons in the process. This definition places the term within the P-type ATPase family, which is characterized by a conserved aspartyl-phosphate intermediate during the catalytic cycle.
Why Is P-type manganese transporter activity Important in Cell Biology?
P-type manganese transporter activity is important because manganese is both essential and toxic, and its intracellular concentration must be maintained within a narrow range [2,5]. By using ATP to drive Mn2+ efflux, these transporters protect cells from manganese overload and contribute to metal homeostasis, antioxidant defense, and cellular signaling [2,5]. In pathogens such as Mycobacterium tuberculosis, P-type ATPase-mediated efflux supports resistance to host-derived metal stress and antibiotics. In humans, mutations or dysregulation of P-type ATPases such as ATP13A2 are associated with Parkinson's disease, highlighting the clinical relevance of this activity. In plants, P-type ATPases influence manganese uptake, transport, and tolerance to excess manganese, affecting crop yield and phytoremediation [5,8].
• Maintains manganese homeostasis by preventing toxic Mn2+ accumulation.
• Supports bacterial metal resistance and virulence in pathogens like Mycobacterium tuberculosis.
• Contributes to plant manganese transport and antioxidant responses under stress.
• Links to Parkinson's disease through the P-type ATPase ATP13A2.
• Provides a mechanism for primary active transport that is distinct from secondary transporters.
• Serves as a target for understanding metal-related drug resistance.
• Helps explain how cells couple ATP hydrolysis to ion gradient formation.
• Influences rhizosphere metal dynamics and phytoremediation potential.
• Is relevant to calcium and manganese cross-talk in plant signaling.
• Offers a model system for studying P-type ATPase structure-function relationships [2,3].
What Happens During P-type manganese transporter activity?
Substrate binding and phosphorylation
In simple terms: The transporter grabs a manganese ion and a molecule of ATP, then uses part of the ATP to tag itself.
In the first step of the P-type ATPase cycle, the transporter binds Mn2+ from the cytoplasmic side and ATP. The conserved aspartate residue in the phosphorylation domain is transiently phosphorylated, forming a high-energy acyl-phosphate intermediate. This phosphorylation event drives a conformational change that occludes the metal ion and prepares it for translocation across the membrane.
Conformational change and ion translocation
In simple terms: The transporter changes shape to push the manganese ion through the membrane.
Following phosphorylation, the transporter undergoes a large conformational rearrangement from the E1 to the E2 state, which moves the bound Mn2+ across the membrane and releases it to the extracellular or luminal side. This step is coupled to the counter-transport of protons, as indicated by the reaction ATP + H2O + Mn2+(in) = ADP + H+ + Mn2+(out) + phosphate. The E2 state has lower affinity for Mn2+, allowing release of the ion.
Dephosphorylation and resetting
In simple terms: The transporter cuts off the phosphate tag and returns to its starting shape.
After Mn2+ release, the aspartyl-phosphate bond is hydrolyzed, releasing inorganic phosphate and returning the transporter to the E1 conformation. This dephosphorylation step is the rate-limiting step in many P-type ATPases and is regulated by the lipid environment and interacting proteins. The cycle is then ready to bind a new Mn2+ ion and ATP.
Lipid-dependent regulation of the cycle
In simple terms: Fats in the membrane can switch the transporter on or off.
The activity of P-type ATPases such as ATP13A2 is modulated by membrane lipids, including phosphatidic acid and phosphatidylinositol phosphates. A lipid switch mechanism can unlock the transporter and stimulate its catalytic cycle, linking membrane composition to manganese transport. This regulation is important for adapting transport rates to cellular metabolic states.
Key Genes Involved in GO:0140613 P-type manganese transporter activity
The following genes and proteins are representative of P-type manganese transporter activity or closely related metal-transport functions, based on published literature [1,2,3,5,7,8].
| Gene | Major Role | Research Relevance |
|---|---|---|
| ATP13A2 | Human P-type ATPase linked to Parkinson's disease; lipid-regulated | Neurodegeneration, lysosomal function, metal homeostasis |
| M. tuberculosis efflux ATPases | Contribute to metal resistance and effluxosome function | Tuberculosis pathogenesis and drug resistance |
| ECA (plant P-type ATPase) | Calcium/manganese transport in plants | Plant stress responses and ion homeostasis |
| ACA (plant P-type ATPase) | Calcium ATPase with roles in stress | Plant calcium and manganese signaling |
| Nramp-related genes | Transport of magnesium and related metals | Bacterial metal transport mechanisms |
| NTPDase (ER) | Nucleoside triphosphate diphosphohydrolase in ER | Endoplasmic reticulum function and nucleotide signaling |
| Manganese transporter genes (plants) | Uptake and transport of manganese | Antioxidant response and manganese toxicity |
| Rhizosphere bacterial transporters | Assist phytoremediation of metals | Environmental metal cycling |
| P-type ATPase superfamily members | General ion transport with phosphorylated intermediate | Comparative transport biology |
| Mn2+ efflux pumps | Export manganese to prevent toxicity | Metal homeostasis and resistance |
| ATP13A2 orthologs | Conserved P-type ATPase function | Model organism studies of Parkinson's disease |
| Bacterial P-type ATPases | Metal efflux in pathogens | Antibiotic and metal resistance |
| Plant ECA/ACA isoforms | Calcium and manganese transport | Crop improvement and stress tolerance |
| Nramp family proteins | Divalent metal transport | Host-pathogen metal competition |
| ER NTPDase | Nucleotide hydrolysis in ER | ER homeostasis and secretion |
| Manganese homeostasis regulators | Coordinate uptake and efflux | Systems biology of metal homeostasis |
| Effluxosome components | Extracellular efflux machinery | Mycobacterial survival strategies |
How Is P-type manganese transporter activity Regulated?
P-type manganese transporter activity is regulated at multiple levels. In ATP13A2, membrane lipids such as phosphatidic acid and phosphoinositides act as a lipid switch that unlocks the transporter and stimulates its activity. In plants, the expression of P-type ATPase genes such as ECA and ACA isoforms is modulated by calcium and manganese stress, suggesting transcriptional regulation. In bacteria, efflux systems including P-type ATPases are induced in response to metal stress and contribute to resistance. Additionally, the catalytic cycle itself is regulated by the phosphorylation/dephosphorylation equilibrium, which can be influenced by interacting proteins and the membrane environment.
P-type manganese transporter activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ATP13A2 | Parkinson's disease | Knockout and point-mutation cell models |
| M. tuberculosis efflux ATPases | Tuberculosis and metal resistance | Bacterial knockout and overexpression strains |
| Plant ECA/ACA | Manganese stress and ion homeostasis | Plant knockout and overexpression lines |
| Nramp-related genes | Metal transport and host-pathogen interactions | Knockout cell lines and bacterial mutants |
| NTPDase | ER function and nucleotide signaling | Knockdown and overexpression models |
Parkinson's disease and ATP13A2
Mutations in ATP13A2, a P-type ATPase, cause a rare form of early-onset Parkinson's disease, and the protein is regulated by a lipid switch that controls its transport activity. This links P-type manganese transporter activity to neurodegeneration, possibly through impaired lysosomal function and metal homeostasis.
Tuberculosis and metal resistance
Mycobacterium tuberculosis uses efflux systems, including P-type ATPases, to resist host-imposed metal stress and antibiotics, contributing to pathogenesis. Understanding these transporters may inform new therapeutic strategies against tuberculosis.
Plant manganese toxicity and phytoremediation
In plants, P-type ATPases help manage manganese transport and antioxidant responses under excess manganese, affecting growth and stress tolerance. Rhizosphere bacteria also assist phytoremediation of metal-contaminated soils, highlighting environmental relevance.
From P-type manganese transporter activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of ATP13A2 alter manganese efflux? | ATP13A2 knockout cell line |
| How do point mutations affect P-type ATPase activity? | Point-mutation knock-in cell models |
| Can overexpression of a P-type ATPase increase metal resistance? | Overexpression cell lines |
| Where is the transporter localized? | Tagged knock-in with fluorescent protein |
| What genes interact with the transporter? | CRISPR library screening |
| How does manganese stress affect plant P-type ATPases? | Plant knockout and overexpression lines |
How to Study the P-type manganese transporter activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ATPase activity assay | ATP hydrolysis rate | Enzymatic characterization |
| Metal flux assay | Mn2+ transport across membranes | Functional validation |
| CRISPR knockout | Gene function loss | Phenotypic screening [1,3] |
| Fluorescence microscopy | Protein localization and metal distribution | Cell biology |
| RNA-seq | Gene expression changes | Stress response studies |
| Proteomics | Protein abundance and interactions | Pathway analysis |
| Bioinformatics | Sequence and structural predictions | Gene annotation |
Transport assays
Direct measurement of ATP-dependent Mn2+ transport can be performed using membrane vesicles or reconstituted proteoliposomes, monitoring ATP hydrolysis and metal flux. These assays are essential to confirm P-type manganese transporter activity.
Genetic knockout and knockdown
CRISPR-Cas9 knockout or RNA interference knockdown of candidate P-type ATPase genes allows assessment of their role in manganese homeostasis and stress responses [1,3]. Phenotypic readouts include metal sensitivity, growth, and survival.
Fluorescence imaging
Fluorescent metal sensors and tagged transporters can be used to visualize Mn2+ distribution and protein localization in live cells [2,3]. This helps link transporter activity to cellular metal dynamics.
Omics and bioinformatics
Transcriptomics, proteomics, and genome-wide association studies can identify P-type ATPase genes and regulatory networks involved in manganese transport [4,8]. Bioinformatics tools predict transmembrane domains and phosphorylation sites.
How CRISPR Can Be Used to Study GO:0140613 P-type manganese transporter activity
Knockout
CRISPR knockout of P-type manganese transporter genes, such as ATP13A2, can reveal their role in manganese efflux and cellular stress responses. Knockout models are useful for testing metal sensitivity and neurodegeneration-related phenotypes.
Point Mutation
Introducing disease-associated point mutations into P-type ATPase genes via CRISPR base editing or homology-directed repair allows study of how specific residues affect transport activity and lipid regulation. This is particularly relevant for ATP13A2 mutations linked to Parkinson's disease.
Knock-in
Knock-in of fluorescent or affinity tags into endogenous P-type ATPase loci enables real-time tracking of transporter localization and dynamics. Tagged knock-in models help dissect membrane trafficking and assembly.
Overexpression
CRISPR activation or cDNA overexpression of P-type manganese transporters can increase metal efflux capacity and confer resistance to manganese stress. Overexpression models are valuable for biochemical purification and structural studies.
How EDITGENE Supports P-type manganese transporter activity Research
Researchers studying P-type manganese transporter activity-related genes often need to determine whether a candidate gene is causally involved in metal transport, disease, or stress resistance. EDITGENE provides a comprehensive suite of CRISPR-based services to generate precisely engineered cell models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for P-type manganese transporter activity research.
Frequently Asked Questions About P-type manganese transporter activity
What is P-type manganese transporter activity?
It is an ATP-dependent molecular function that pumps manganese ions (Mn2+) out of a cell or organelle, defined as GO:0140613.
What genes are involved in P-type manganese transporter activity?
Genes include ATP13A2 in humans, bacterial efflux ATPases, and plant ECA/ACA isoforms [1,3,8].
What is the reaction catalyzed by P-type manganese transporters?
ATP + H2O + Mn2+(in) = ADP + H+ + Mn2+(out) + phosphate.
How is P-type manganese transporter activity regulated?
It is regulated by phosphorylation, membrane lipids such as phosphatidic acid, and stress-responsive transcription [2,3,8].
Which diseases are linked to P-type manganese transporters?
Parkinson's disease via ATP13A2 and tuberculosis via bacterial efflux ATPases [1,3].
What is the role of ATP13A2 in Parkinson's disease?
ATP13A2 is a lipid-regulated P-type ATPase whose mutations cause early-onset Parkinson's disease.
How can I study P-type manganese transporter activity in the lab?
Use ATPase assays, metal flux assays, CRISPR knockout, and fluorescence imaging [2,3].
What model systems are used for P-type manganese transporter research?
Human cell lines, Mycobacterium tuberculosis, and plant models [1,3,8].
What are the synonyms for GO:0140613?
No synonyms are listed in QuickGO for this term.
Why is manganese transport important for cells?
Manganese is essential but toxic in excess, so efflux transporters maintain homeostasis and protect against stress [2,5].
Conclusion
P-type manganese transporter activity (GO:0140613) is a fundamental molecular function that couples ATP hydrolysis to manganese efflux, protecting cells from metal toxicity and maintaining homeostasis. Its roles in bacterial pathogenesis, plant stress responses, and human neurodegenerative disease make it a compelling target for basic and translational research [1,3,5]. Advances in CRISPR-based models and bioinformatics will continue to illuminate the mechanisms and regulation of this important transporter family [2,3].
References
- 1. Benastre L et al.. 2026. Effluxosomes and the evolution of metal resistance in Mycobacterium tuberculosis.. Infect Immun 94(8):e0030726 PMID: 42360134
- 2. Pittman JK. 2005. Managing the manganese: molecular mechanisms of manganese transport and homeostasis.. New Phytol 167(3):733-42 PMID: 16101910
- 3. Holemans T et al.. 2015. A lipid switch unlocks Parkinson's disease-associated ATP13A2.. Proc Natl Acad Sci U S A 112(29):9040-5 PMID: 26134396
- 4. Xiao Y et al.. 2022. Role of the rhizosphere bacterial community in assisting phytoremediation in a lead-zinc area.. Front Plant Sci 13:1106985 PMID: 36874912
- 5. Yang ZB et al.. 2007. [Manganese uptake and transportation as well as antioxidant response to excess manganese in plants].. Zhi Wu Sheng Li Yu Fen Zi Sheng Wu Xue Xue Bao 33(6):480-8 PMID: 18349501
- 6. Ostuni MA et al.. 2009. Characterization of a functional NTPDase in the endoplasmic reticulum of rat submandibular salivary gland.. Physiol Res 58(6):843-854 PMID: 19093741
- 7. Shin JH et al.. 2014. Transport of magnesium by a bacterial Nramp-related gene.. PLoS Genet 10(6):e1004429 PMID: 24968120
- 8. Aslam R et al.. 2017. Genome-wide analysis of wheat calcium ATPases and potential role of selected ACAs and ECAs in calcium stress.. BMC Plant Biol 17(1):174 PMID: 29078753
